Ixempra® (International non-propriety name (INN): ixabepilone) is an injectable antineoplastic agent belonging to the epothilone class. It is a synthetic derivative of the natural product epothilone B (a.k.a., EpoB), with the macrolide ring oxygen atom replaced with a nitrogen atom to give the corresponding macrolactam. The chemical name of ixabepilone (a.k.a., aza-EpoB, azaepothilone B and BMS-247550) is ((1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.

Ixabepilone is a white to off-white powder with a molecular formula of C27H42N2O5S and a molecular weight of 506.70. Ixabepilone was developed by Bristol-Myers Squibb and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic breast cancer on Oct. 16, 2007. It is a cytotoxic microtubule stabilizer and the first member of the epothilone family of anticancer agents to be approved.
Analogues E-Epo C-lactam, Epo A-lactam, Epo F-lactam, Z-Epo C-lactam, Z-Epo D-lactam, E-Epo D-lactam of ixabepilone have also been reported (see J. Am. Chem. Soc. 2000, 122, 8890-8897). The C15 epimer (a.k.a., 15-epi-aza-dEpoB, 15-epi-12,13-desoxy-15-azaepothilone B and 15-epi-15-azaepothilone D) of Z-Epo D-lactam has also been reported (Org. Lett. 2000, 2, 1637-1639).

U.S. Pat. No. 6,605,599 (the '599 patent) describes two approaches for synthesizing azaepothilones such as ixabepilone. One synthetic strategy to prepare the azaepothilone is based on a ring-closing olefin metathesis (RCM) reaction to cyclise a linear amide compound into a macrocyclic lactam (a.k.a., a macrolactam).
The '599 patent also discloses the preparation of amine derivatives 20 from aldehyde 18 (a commercially available compound) as shown in Scheme 1. Imine derivative 19 is treated with an allylating reagent such as allylmagnesium bromide. The '599 patent, however, does not describe the preparation of a homochiral form of amine derivative 20, nor does R15 include any chiral auxiliary compounds.
The '599 patent also discloses a method for azaepothilone synthesis from epothilones as shown in Scheme 2. Compounds 103 can be prepared from compounds 5 by reaction with a palladium complex followed by treatment with sodium azide. Subsequent reduction of compounds 103 provides compounds 104. Finally, compounds 5 are obtained by macrolactamization of compounds 104. This procedure was used to prepare ixabepilone from the natural product epothilone B (a.k.a., EpoB, patupilone, EPO 906) in a step-wise approach in a 13-21% overall yield or a 23% overall yield in a one-pot, three-step protocol (J. Am. Chem. Soc. 2000, 122, 8890-8897).
U.S. Pat. No. 6,365,749 discloses a process to produce ring opened epothilone derivatives 1 from epothilones 3 as shown in Scheme 3. The epothilone derivatives 3 can be treated with a palladium catalyst and nitrogen-based nucleophile to provide ring opened epothilone derivatives 1. When X is NH2, the derivatives can be macrolactamized to produce azaepothilones.
U.S. Pat. No. 6,518,421 discloses the conversion of epothilones into azaepothilones as shown in Scheme 4 comprising macrolactone ring opening of epothilones 3 to provide ammonium carboxylate salts and subsequent macrolactamization to afford azaepothilones 2. This can be stepwise or in a single reaction vessel without isolation of the salt intermediate, and can be used to convert epothilone B to ixabepilone.
A total synthesis method for the preparation of ixabepilone was disclosed in U.S. Pat. No. 6,867,305 and J. Org. Chem. 2001, 66, 4369-4378. This approach comprises B-alkyl Suzuki coupling of fragments D1 and a borane derivative of alkene D2 (Scheme 5). D1b was coupled with borane derivative of alkene D2c in 78% yield using a Suzuki coupling, then converted to ixabepilone in a process requiring an additional 8 synthetic steps, including macrolactamization. The Suzuki coupling of the N—BOC amine derivative IIIa′ or the azide derivative D1b with D2a gave only 10% and 63% yields in the Suzuki reaction, respectively.
It was believed that the low yield in the coupling of IIIa′ was due to the presence of the N—BOC (BOC is tert-butyloxycarbonyl; CO2t-Bu; t-BuOCO) carbamate group. This was seemingly supported when an improved 63% yield was obtained by substituting the N—BOC carbamate group of vinyl iodide IIIa′ with an azide, as in azido vinyl iodide D1b. However, in all cases the arsenic-based ligand AsPh3 was used in the B-alkyl Suzuki reaction. Arsenic is toxic, and the use of arsenic-based reagents is to be highly avoided in API manufacturing processes due to strict requirements on the levels of arsenic that are allowed in drug substances (≦2 ppm) for human consumption. Accordingly, if arsenic-based reagents are used in the manufacture of an API, a significant (and costly) burden is placed on the manufacturer to control the level of arsenic to acceptable levels. It is therefore preferable to avoid the use of arsenic-based reagents in API manufacture.
In view of the above, there remains a need for a process for the manufacture of ixabepilone and its derivatives that does not reply upon the use of epothilones, which are natural products, as starting materials. There is also a need for a process for the manufacture of ixabepilone that requires fewer chemical steps following formation of the complete acyclic precursor of ixabepilone as compared to the relevant art.